Preparation of fluorinated compounds

ABSTRACT

A method for the preparation of a fluorinated Phosphonate having the formula (RO) 2 PO CFR′R″ comprises treating a phosphonate of the formula (RO) 2 PO CHR′R″, or a metal salt thereof, with fluorine. R is an alkyl group R′ is hydrogen or alkyl and R″ is hydrogen, alkyl or another group.

This invention relates to the preparation of fluorinated compounds and,in particular, to the preparation of fluorophosphonates.

Trialkylphosphonoacetates and related phosphonates are valuableintermediates in organic syntheses. The corresponding monofluorinatedcompounds have the potential to be equally valuable and the chemistry ofone of them, (EtO)₂PO.CHF.COOEt, has been developed extensively by H.Machleit and R. Westenden (Lieb. Amr. Chem, 1964, 674, 1), D. J. Burtonet. al. (J. Org. Chem., 1990, 55, 2311; J. Org. Chem., 1990, 55, 4639;J. Org. Chem., 1991, 56,273, J. Org. Chem., 1994, 59, 7085; Phosphorus,Sulphur and silicon, 1995, 105, 205; J. Fluorine Chem., 1996, 77, 45),R. S. H. Lui et. at. (J. Am Chem. Soc. 1981, 103, 7195) and P. W.Collins et. al. (J. Med. Chem., 1987, 30, 1952).

Most of the material used in these investigations has been prepared byreaction between a trialkylphosphate and ethyl bromofluoroacetate(Arbutzov Reaction and modifications thereof), but while the Arbutzovreaction itself can be carried out in high yield, the preparation ofethyl bromofluoroacetate is a multi-step synthesis. Further, the bromocompounds required to make other fluorinated phosphonates are notreadily available. More recently, the lithium salt derived fromtriethylphosphonoacetate has been treated with the electrophilicfluorinating agent, N-fluoro-o-benzene-disulphonimide (F. A. Davis, W.Han and C. K. Murphy, J. Org. Chem. 1995, 60, 4730) to produce themonofluoro derivative. However, the fluorinating agent is expensive toprepare and is not readily available.

Additionally, the use of electrophilic fluorinating agents such asN-fluoro-1,4-diazabicyclo[2.2.2]octane in the selective fluorination ofvarious methylenephosphonate and methylenephosphorane derivates isdiscussed in U.S. Pat. No. 5,442,084 but, again, fluorinating agents ofthis type are generally not readily available.

A more convenient and economical technique for the fluorination oforganic compounds is via the use of elemental fluorine. However,reactions of this type can be difficult to control in view of the highreactivity of elemental fluorine, although some applications have beensuccessful. Thus PCT Application No WO97/00848 discloses the preparationof certain fluorinated esters from the corresponding hydrogenated estersby reaction with elemental fluorine, and a similar technique is appliedto various 1,3-diketones and 1,3-ketoesters to obtain the correspondingfluorinated derivatives in PCT Application No WO95/14646. Suchprocedures are, however, rarely satisfactory and generally, lead tounspecific multiple substitution of the starting material, carbon-carbonbond cleavage and oxidation.

Surprisingly in the light of the prior art, the present inventors havenow disclosed that fluorinated phosphonates can be prepared by treatinga salt derived from the parent phosphonate, or by treating the parentphosphonate in the presence of a base, with elemental flurorine.

According to the present invention there is provided a method for thepreparation of a fluorinated phosphonate having the formula(RO)₂PO.CFR′.R″ comprises treating a phosphonate of the formula(RO)₂PO.CHR′R″, or a metal salt thereof, with fluorine, where R is analkyl group, R′ is hydrogen or alkyl and R″ is hydrogen, alkyl oranother group.

Preferably the metal salt is prepared by treatment of (RO)₂PO.CHR′R″with an alkali metal hydride or an alkali metal alkoxide. Preferably thephosphonate of formula (RO)₂PO.CHR′R″ is treated with fluorine in thepresence of a base.

It is preferred that the group R has from 1-6 carbon atoms and that inthe case where R′ is alkyl, it has from 1-6 carbon atoms. Where R″ is agroup other than hydrogen, it is preferably —PO(OR)₂, —COOR, —COOR,—CO.R or —CN.

Preferably the metal salt has the formula (RO)₂PO.C⁻R′R″.M⁺ where M islithium, sodium or potassium.

Preferably, the fluorine is diluted with an inert gas such as nitrogen,helium or argon. The concentration of fluorine is preferably in therange 1-50% v/v, more preferably from 2-25% v/v and most preferably from5-15% v/v.

Preferably, the fluorination is carried out in a solvent which issubstantially inert to fluorine, such as acetonitrile or propionitrile.

Preferably, the alkali metal salts are formed in acetonitrile but theymay also be formed in a solvent such as diethyl ether, tetrahydrofuraneor dimethoxyethane. If solvents such as these are used in the formationof the metal salts, it is necessary for acetonitrile or propionitrile tobe added and the ether to be removed by distillation before thefluorination is undertaken.

Where fluorination is carried out by passing a stream of dilutedfluorine into a solution of the phosphonate in the presence of a base,the solvent is preferably dry acetonitrile and the base is anhydrouspotassium fluoride or anhydrous caesium fluoride.

Preferably, the concentration of phosphonate in the solvent is from 0.1molar to 10 molar, although higher concentrations may be used.

Preferably, the reaction is carried out at a temperature in the range−60° C. to +150° C., more preferably from −20° C. to +50° C. and mostpreferably from −10° C. to +15° C.

The following examples serve to illustrate the present invention. Exceptwhere indicated otherwise, ¹H, ¹⁹F and ³¹P NMR spectra were recorded ona Bruker AC250 spectrometer operating at 250 MHz for hydrogen, 235 MHzfor fluorine or 101 MHz for phosphorus. ¹³C NMR spectra were measured ona Varian VXR 400 spectrometer operating at 100 MHz or a Varian Gemini200 spectrometer operating at 50 MHz. Chemical shifts are recorded inppm from tetramethyl silane, fluorotrichloromethane and phosphoric acid,and coupling constants are in Hz. Mass spectra were measured on a FisonsTrio 1000 mass spectrometer coupled to a Hewlett Packard 5890 II gaschromatograph fitted with a silicone elastomer coated column (SE 30; 25m., 0.2 mm. i.d.).

EXAMPLE 1

Fluorination of Triethyl Phosphonoacetate

A glass reaction vessel, fitted with a stirrer was purged with nitrogenand charged with sodium hydride (1.1 gm in oil, i.e. 0.66 gm. 30 mmol.NaH). While maintaining the nitrogen atmosphere, hexane was added to thesodium hydride, the mixture was slurried to wash off the oil, and thenthe hexane solution was removed with a syringe. Dry acetonitrile wasthen added to the sodium hydride followed by triethyl phosphonoacetate(4.48 gm, 20 mmol.) which was added dropwise to the stirred slurry.Stirring was continued for one hour before the mixture was cooled to ca.0° C. and fluorine (50 mmol diluted to 10% v/v with nitrogen) was passedthrough over a period of 4 hours. After this time, the fluorine wasswitched off, and the reaction vessel was purged with nitrogen. Aweighed amount of trifluoromethyl benzene was then added to the reactionproduct and from the ¹⁹F and ³¹P nmr spectra, the amount of recoveredstarting material and the amount of products formed was calculated. Thereaction mixture was poured into water and extracted intodichloromethane. Removal of the solvent gave a mixture of startingmaterial and products which were purified by column chromatography(SiO₂/ethyl acetate). The products were i) Triethyl1-fluorophosphonoacetate (HRMS, Found: (M+NH₄)⁺ 260.1063. C₈H₂₀FNO₅Prequires 260.1063); δ_(F)-211 (dd,²J_(F,P) 71.9, J_(H,F) 46.8); δ_(H)1.3 (9H, m), 4.3 (6H, m), 5.2(1H, dd, J_(H,F) 46.8, J_(H,P) 11.7); δ_(P)10.3 (d, J_(F,P) 71.9), δ_(C) (100 MHz)13.5 (s, COOCH₂CH₃), 15.8(d,³J_(C,P) 5.7, OCH₂CH₃), 61.8 (s, COOCH₂CH₃), 63.7 (t,²J_(C,P)=⁴J_(C,F) 6.3, OCH₂CH₃), 84.4 (dd, ¹J_(C,F) 195, ¹J_(C,P) 158,CHF), 164.3 (d, ²J_(C,F) 21.7, CO); m/z (CI⁺, NH₃) 260 ((M+NH₄)⁺, 100%),243 (M+1, 80) and ii) Triethyl 1,1-difluorophosphonoacetate (HRMS,Found: (M+NH₄)⁺278.0969. C₈H₁₉F₂NO₅P requires 278.0969); δ_(F)-117 (d,²J_(F,P) 96.2); δ_(H) 1.4 (9H, m), 4.4 (6H, m); δ_(P) 2.96 (t, J_(F,P)96.2), δ_(C) (100 MHz)13.4 (s, COOCH₂CH₃), 15.9 (d,³J_(C,P) 5.3,OCH₂CH₃), 63.4 (s, COOCH₂CH₃), 65.2 (d, ²J_(C,P) 6.5, OCH₂CH₃), 110.7(dt, ¹J_(C,F) 271, ¹J_(C,P) 203, CF₂), 161.4 (q, ²J_(C,F) 18.3, CO); m/z(CI⁺, NH₃) 278 ((M+NH₄)⁺, 100%), 261 (M+1, 20). In this example theconversion was calculated to be 90%, the yield of the monofluorinatedphosphonate was 35% and the difluorophosphonate was 15%.

EXAMPLE 2

Fluorination of Triethyl 2-phosphonopropionate

In a similar manner to that described in Example 1, triethyl2-phosphonopropionate was fluorinated to give triethyl2-fluoro-2-phosphonopropionate (HRMS, Found: (M+NH₄)⁺274.1220.C₉H₂₂FNO₅P requires 274.1220); δ_(F)-172 (dq, ²J_(F,P) 83.3, ³J_(H,F)23.4); δ_(H) 1.3 (9H, m), 1.8 (3H, d,d J_(H,F) 23.4, J_(H,P) 15.1), 4.2(6H, m); δ_(P) 13.4 (d, ²J_(F,P) 83.3), δ_(C) (100 MHz)13.7 (s,COOCH₂CH₃), 16.1 (s, OCH₂CH₃), 19.9 (d, ²J_(C,F) 21.8 CH₃CF), 62.1 (s,COOCH₂ CH₃), 64.0 (dd, ²J_(C,P) 19.1, ⁴J_(C,F) 6.5 OCH₂CH₃), 92.7 (dd,¹J_(C,F), ¹J_(C,P) 165 and 193. CF), 167.6 (dd, ²J_(C,F) 22.5, ²J_(C,P)4.9 CO); m/z (CI⁺, NH₃) 274 ((M+NH₄)⁺, 100%), 257 (M+1, 99). Theconversion of starting material was 70% and the yield was 35%.

EXAMPLE 3

Fluorination of Tetraisopropyl Methylenediphosphonate

In a similar manner to that described in Example 1, tetraisopropylmethylenediphosphonate was fluorinated to give i) tetraisopropylfluoromethylenediphosphonate (HRMS, Found: (M+NH₄)⁺ 380.1767.C₁₃H₃₃FNO₆P₂ requires 380.1767); δ_(F)-227 (dt, J_(H,F) 46, ²J_(F,P)64); δ_(H) 1.37(12H, d, J_(H,H) 6.2), 1.38 (12H, d, J_(H,H) 6.2), 4.8(5H, m); δ_(P) 9.7 (d, ²J_(F,P) 64), δ_(C) (100 MHz)23.6 (m, CH₃), 24.1(d, ³J_(C,P) 11.9, CH₃), 72.7 (d, ²J_(C,F) 37.8, CH(CH₃)), 84.3 (dt,¹J_(C,F) 191.5, ¹J_(C,P) 158, CFH); m/z (CI⁺, NH₃) 380 ((M+NH₄)⁺, 24%),363 (M+1, 100), and ii) tetraisopropyl difluoromethylenediphosphonate(HRMS, Found: (M+NH₄)⁺398.1673. C₁₃H₃₂F₂NO₆P₂ requires 398.1673);δ_(F)-123 (t, ²J_(F,P) 87); δ_(H) 1.44 (12H, d, J_(H,H) 6.2), 1.46 (12H,d, J_(H,H) 6.2), 4.97 (4H, m); δ_(P) 2.3 (t, ²J_(F,P) 87), δ_(C) (100MHz) 23.5 (s, CH₃), 24.1 (s, CH₃), 74.6 (s, CH(CH₃)), 115.5 (tt,¹J_(C,F) 278.8, ¹J_(C,P) 189.6, CF₂); m/z (CI⁺, NH₃) 398 ((M+NH₄)⁺,39%), 381 (M+1, 100). The conversion of starting material was 73%, theyield of the monofluoro phosphonate was 50% and the yield of difluorophosphonate was 10%.

EXAMPLE 4

Fluorination of Dimethyl-2-oxypropyl Phosphonate

A stirred glass reaction vessel charged with dry acetonitrile (50 ml),anhydrous potassium fluoride (5 gm) and dimethyl-2-oxypropyl phosphonate(3.32 gm., 20 mmol) under an atmosphere of dry nitrogen was cooled toca. 0° C. Fluorine (65 mmol) diluted to 10% v/v was then passed throughthe mixture over a period of 5 hours. After this treatment, the mixturewas filtered and the solids were washed with acetonitrile. The yieldsand conversion were calculated as in example 1 by adding a weighedamount of trifluoromethyl benzene to the combined filtrate and measuringthe ¹⁹F and ³¹P nmr spectra. The product, dimethyl-1-fluoro-2-oxypropylphosphonate (HRMS, Found: (M+NH₄)⁺ 202.0644. C₅H₁₄FNO₄P requires202.06445); δ_(F)-208 (d,d,q, ²J_(F,P) 71.3, ²J_(HF) 47.8, ⁴J_(HF) 4.5);δ_(H) 2.39 (3H, d, ⁴J_(H,F) 4.5, CO.CH₃), 3.9 (6H, d, d, ²J_(H,P) 10.8,J 2.9, CH₃OP), 5.25 (1H, d,d, ²J_(H,F) 47.7, ²J_(H,P) 14.4, CHF); δ_(P)12.7 (d, ²J_(F,P) 71.2), δ_(C) (50 MHz) 26.5 (s, CH₃O.C), 54.2 (d,d,²J_(C,P) 6.6, ⁴J_(C,F) 2.0, CH₃OP), 91.0 (d,d, ¹J_(C,F) 196.5, ¹J_(C,P)152.5, CHF), 200.5 (d, ²J_(C,F) 20.2, CFHCO); m/z (CI⁺, NH₃) 202((M+NH₄)⁺, 10%), 128 (100), was isolated as described in example 1. Theconversion was 50% and the yield was 28%.

EXAMPLE 5

Fluorination of Dimethyl-2-oxypropyl Phosphonate

A stirred glass reaction vessel charged with dry acetonitrile (70 ml),sodium ethoxide (1.6 gm., 23 mmol) and dimethyl-2-oxypropyl phosphonate(3.32 gm., 20 mmol) under an atmosphere of dry nitrogen was stirred for1 hour and room temperature, then cooled to ca. 0° C. Fluorine (65 mmol)diluted to 10% v/v was passed through the mixture over a period of 5hours. After this treatment the yields and conversion were calculated,as in example 1, by adding a weighed amount of trifluoromethyl benzeneto the reaction product and measuring the ¹⁹F and ³¹P nmr spectra. Theproduct, dimethyl-1-fluoro-2-oxypropyl phosphonate, was isolated asdescribed in example 1. The conversion was 28% and the yield was 40%.

What is claimed is:
 1. The method for the preparation of a fluorinatedphosphonate having the formula (RO)₂PO.CFR′.R″ comprises treating aphosphonate of the formula (RO)₂PO.CHR′R″, or a metal salt thereof, withfluorine, where R is an alkyl group, R′ is hydrogen or alkyl and R1″ ishydrogen, alkyl or a —PO(OR)₂, —COOR, —CO.R or —CN group.
 2. The methodaccording to claim 1 wherein the metal salt is prepared by treatment of,(RO)₂PO.CHR′R″ with an alkali metal hydride or an alkali metal alkoxide.3. The method according to claim 1 wherein a phosphonate of formula(RO)₂PO.CHR′R″ is treated with fluorine in the presence of a base. 4.The method according to claim 1, wherein the group R has from 1-6 carbonatoms and, in the case where R′ is alkyl, it has from 1-6 carbon atoms.5. The method according to claim 1 wherein the metal salt is a salt oflithium, sodium or potassium.
 6. The method according to claim 1 whereinthe fluorine is diluted with an inert gas.
 7. The method according toclaim 6 wherein the fluorine is used in a concentration in the range1-50% v/v.
 8. The method according to claim 7 wherein the concentrationof fluorine is from 2-25% v/v.
 9. The method according to claim 8wherein the concentration of fluorine is from 5-15% v/v.
 10. The methodaccording to claim 1 wherein the fluorination is carried out in asolvent which is substantially inert to fluorine.
 11. The methodaccording to claim 10 wherein the solvent is acetonitrile orpropionitrile.
 12. The method according to claim 1 wherein the reactionis carried out in a solvent and the concentration of phosphonate in thesolvent is from 0.1 molar to 10 molar.
 13. The method according to claim1 wherein the reaction is carried out at a temperature in the range −60°C. to plus 150° C.
 14. The method according to claim 13 wherein thereaction temperature is from −20° C. to +50° C.
 15. The method accordingto claim 14 wherein the reaction temperature is from −10° C. to +15° C.